Expression and function of regulator of G-protein signaling 10 (RGS10) in ovarian cancer and microglia
Ali, Mourad Wagdy Ahmed
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G-Protein coupled receptors (GPCRs) mediate a wide array of cellular functions, such as cell proliferation, migration, and survival. Regulators of G-protein signaling (RGS) proteins are a diverse family of proteins that regulate signaling pathways downstream of GPCRs by acting on G-proteins. The focus of this dissertation is on the regulation of G-protein pathways in cancer and inflammation by RGS proteins, particularly by RGS10. We focused on signaling initiated by two related receptor families, lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) receptors, which are implicated in ovarian cancer and neuroinflammation, respectively. Aberrant expression and mutations in RGS proteins have been implicated in diseases such as cancer and autoimmune disorders. The aim of this study was to define the function and the expression of RGS proteins, particularly RGS10, in ovarian cancer and microglia. LPA is the predominant growth factor in ovarian cancer, promoting proliferation, migration, and survival. RGS proteins negatively regulate LPA-mediated effects in ovarian cancer. We determined that RGS proteins, RGS10 and RGS17 regulate LPA-mediated survival in ovarian cancer cells. Specifically, our data demonstrate that RGS10 and RGS17 negatively regulate LPA-mediated AKT survival pathway in ovarian cancer cells. Further, we show that RGS10 and RGS17 are down-regulated in chemoresistant ovarian cancer cells, and our results show that RGS10 is epigenetically silenced in chemoresistant ovarian cancer cells via increased DNA methylation and decreased histone acetylation of the RGS10 promoter by DNA methyltransferase 1 (DNMT1), and histone deacetylase 1 (HDAC1), respectively. In addition to its role in chemoresistant ovarian cancer cells, RGS10 has been shown to exert an anti-inflammatory effect in microglia, the brain’s innate immune cells, via blunting pro-inflammatory cytokines signaling, and RGS10 is suppressed in activated microglia. We investigated the mechanism by which RGS10 is down-regulated in activated microglia, as well as the mechanism by which RGS10 regulates signaling pathways in microglia. Our results indicate that RGS10 is epigenetically suppressed via decreased histone acetylation of its promoter in activated microglia. Our results also suggest that RGS10 negatively regulates protein kinase A (PKA) and glycogen synthase kinase-3 beta (GSK-3β) downstream of lipopolysaccharide (LPS) and S1P, which may account for its regulation of pro-inflammatory cytokine signaling in activated microglia.